We conducted a case-control study of ALS in New England in 1993-96. Specific aims were to characterize potential associations of ALS with (i) lead exposure;(ii) exposure to other neurotoxicants, eg, mercury, solvents and pesticides;(iii) lifestyle factors such as cigarette smoking and diet;and (iv) genetic polymorphisms affecting neurologic function or lead metabolism. Cases (N=110) were recruited at two hospitals in Boston, MA. Population controls (N=256) identified by random digit dialing were frequency matched to cases by age, sex, and region of residence within New England. We collected information on occupational, residential, and recreational exposure to lead using a structured interview. In addition, we measured blood and bone lead levels, the latter using in vivo K x-ray fluorescence (K-XRF), and archived whole blood and serum samples for studies of gene-environment interaction. Initial analyses from this study focused on the relationship of ALS to lead exposure. We found that risk of ALS was associated with a 1.9-fold increase in self-reported occupational exposure to lead, with a dose-response for lifetime days of lead exposure. Risk of ALS was also associated with elevations in both blood and bone lead levels: it was increased 1.9-fold for each mg/dl increase in blood lead, 3.6-fold for each doubling of patella lead, and 2.3-foldfor each doubling of tibia lead. These results extend previous reports based entirely on interview data, showing for the first time an association of ALS with lead biomarkers, and suggest a potential role for lead exposure in the etiology of ALS. We also explored the role of genetic susceptibility in ALS. Specifically, we evaluated the relationship of ALS to polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR), which have both been implicated in lead susceptibility. The ALAD 2 allele was associated with decreased lead levels in both patella and tibia, although not in blood, and with 1.9-fold increase in ALS risk. In contrast, the VDR B allele was not associated with lead levels or ALS risk. We also investigated the relationship of ALS to vascular endothelial growth factor (VEGF), an angiogenic growth factor that mediates responses to hypoxia. We confirmed previous reports that risk of ALS is associated with polymorphisms in the VEGF promoter region that determine two specific haplotypes. In a recent analysis, we found no relationship of ALS risk with polymorphisms in XRCC1, an gene important in DNA repair previously suggested to play a role in ALS. We investigated the relationship of ALS to lifestyle factors. Cigarette smoking was associated with 1.7-fold increase in ALS risk, but alcohol use had no relationship to ALS. Overall, dietary intake of antioxidants and minerals was not strongly related to ALS risk, although modestly protective associations were found for magnesium and lycopene. Family history of ALS was associated with increased risk. Head trauma also increased risk of ALS, with a more than 3-fold increase in risk for individuals with more than one head injury or those with a head injury within the 10 years prior to diagnosis;those with both had an 11-fold increase in risk. We studied survival in ALS using information on date and cause of death retrieved from the National Death Index. We found mortality data for 100 of 110 cases;93 of 100 death certificates mentioned ALS. Median survival from diagnosis to death was 28 months. Shorter survival was associated with older age at diagnosis, female sex, bulbar onset, shorter interval between symptom onset and diagnosis, and reduced lung function. Shorter survival from diagnosis to death had a weak inverse association with blood lead (hazard ratio = 0.9;95% confidence interval, 0.81.0) and a stronger inverse association with patella lead (0.5;0.21.0) and tibia lead (0.3;0.10.7);similar results were found for survival from symptom onset to death. These unexpected results suggest that lead exposure is associated with longer survival in ALS cases and, if confirmed, may shed light on mechanisms involved in disease progression. More recently, we have studied ALS using two new data sources. We have collaborated with researchers from the Karolinska Institute on two studies based on Swedish registries. In one, we found that both low and high maternal age were associated with 1.5- to 1.7-fold increase in ALS risk. Further, ALS risk was slightly greater in individuals with more younger siblings, particularly if the latter were born after an interval of at least six years (1.8-fold increase). These results provided some support for the theory that early life exposures might contribute to disease pathogenesis. In a second study, we provided quantitative data on familial risk of ALS, showing that risk was increased 17-fold in siblings of ALS cases and 9-fold in their children. Although increased risk among families of ALS cases is well-established, these quantitative data suggest a strong genetic component to the disease. In the past year, we completed field work and initial data analysis for a new case-control study, the Veterans with ALS and Lead Exposure (VALE) Study, conducted in collaboration with researchers at Duke University and the Durham Veterans Administration Hospital. The VALE study adds a component to an ongoing case-control study of ALS, collecting samples for measurement of heavy metal exposure. In an analysis of 184 ALS cases and 194 matched controls, we found that a doubling of blood lead was associated with a 1.9-fold increase in ALS risk, a result both qualitatively and quantitatively similar to our earlier finding. These results extend our previous work by incorporating adjustment for bone turnover biomarkers into the analysis. The finding that the association of blood lead with ALS risk persists after such adjustment strongly suggests that the association is not a consequence of increased bone turnover among cases, who may be less active than controls. We plan to continue analysis of data from the VALE study, to examine associations of lead with ALS survival, associations of other metals with ALS risk, and the influence of genetic variation.